Imitation may be the sincerest form of flattery, but it can have deadly consequences when practiced by viruses. New research by Dr. Nels Elde, a postdoctoral fellow in the Basic Sciences Division, shows how a key immunity factor evolved to stay effective in the face of mimicry. The study, appearing online in Nature, in advanced of publication, combined evolutionary analysis with experiments in yeast and infections in primate cell lines to gain new insights into how hosts can evolve to deal with the widespread challenge of viral mimicry.

Many viruses mimic host proteins to promote infections. Defeating mimicry is difficult for hosts because these virus genes can evolve rapidly to produce proteins that closely resemble those of the host, rendering them nearly ‘invisible.’ One such case of mimicry involves poxviruses that produce a protein called K3L that resembles the substrate of the protein kinase R (PKR), a vital component of vertebrate immunity. The challenge of mimicry is especially keen for PKR because its substrate, the host protein PKR acts on, hasn’t changed during primate evolution. Therefore, the substrate of PKR is a sitting target for viral mimics that disable its anti-viral activity, including those found in modern poxviruses such as the deadly smallpox and vaccinia, the famous vaccine virus.

“It's like playing a game of rock-paper-scissors, except PKR’s substrate only plays ‘rock’ over and over again," said Dr. Harmit Malik, senior author on the paper. "Obviously, the viral mimic has a huge advantage in this game, so we wondered what PKR might do in terms of its evolution and whether this might counter mimicry.”

The authors found that PKR is one of the fastest evolving genes in the genomes of primates. Strikingly, some of the strongest signals of rapid evolution were localized to regions of PKR involved in recognizing its substrate. The evolutionary analysis suggested that these regions of interaction might be critical for discriminating against viral mimics like K3L.

“One of the nice advantages we had with our project was that PKR has been studied for decades and scientists have developed beautiful experimental tools we could use to test our evolutionary hypotheses,” Elde said.

Experiments using the genetic model organism baker’s yeast, which shares PKR’s substrate, showed that rapid evolution of PKR in primates resulted in some versions of the protein that could discriminate against K3L, while still recognizing an unchanging substrate.

In collaboration with the Human Biology Division's Drs. Adam Geballe and Stephanie Child, the study was extended to infections of primate cell lines with vaccinia virus. Together the experiments showed that PKR evolves in a manner that increases the odds that it can defeat viral mimics. The finding helps explain how PKR can remain an effective immunity factor despite being evolutionarily outpaced by viruses. PKR from humans seems especially resistant to K3L from vaccinia virus, while PKR from other primates is much more susceptible to mimics. This is likely to be the result of evolution against ancient viruses that left the resistant or susceptible versions of PKR found today. Although human PKR seems to defeat K3L, poxviruses produce even more mimics targeting other host processes, so these evolutionary battles continue on several fronts.

The research received funding from Searle Scholar and Burroughs Wellcome investigator awards to Malik and an NIH grant to Geballe. Elde is an Ellison Medical Foundation Fellow of the Life Sciences Research Foundation.